Therapeutic Potentials of a New Long Noncoding RNA in Diabetic Bone Wound Repair

新型长非编码 RNA 在糖尿病骨伤口修复中的治疗潜力

• 批准号: 10684848
• 负责人: JAKE JINKUN CHEN
• 金额: $ 58.9万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-16 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10684848
• 关键词: Antidiabetic Drugs; Binding Proteins; Biocompatible Materials; Biological Process; Biology; Biomechanics; Blood Glucose; Bone Diseases; Bone Regeneration; Bone Resorption; Bone Tissue; Boston; Calcitonin; Cell physiology; Cellular biology; Chondrocytes; Clinic; Clinical Trials; Code; Coin; Complication; Data; Defect; Development; Diabetes Mellitus; Diabetic mouse; Disease; Dose; Drug Delivery Systems; Drug Targeting; Epidemic; Epigenetic Process; Experimental Pathology; Family; Foundations; Functional disorder; Future; Gene Expression; Genes; Health; Hyperglycemia; Impaired wound healing; Incidence; Knockout Mice; Laboratories; Length; Link; Lysine; Methods; Molecular; Molecular Biology; Mus; Natural regeneration; New Jersey; Non-Insulin-Dependent Diabetes Mellitus; Nucleotides; Osteoblasts; Osteoclasts; Osteogenesis; Outcome; PTH gene; Pathogenesis; Pathologic; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Phenotype; Play; RNA; RNA Binding; Research; Research Personnel; Role; Selective Estrogen Receptor Modulators; Site; System; Techniques; Technology; Therapeutic; Therapeutic Effect; Transcript; Transcription Process; Universities; Untranslated RNA; bisphosphonate; bone; bone cell; bone fracture repair; bone healing; bone metabolism; cell type; diabetic; diabetic bone disease; efficacy evaluation; fracture risk; histone methylation; human disease; knockout gene; lipid biosynthesis; loss of function; mouse model; nanoparticle; new therapeutic target; novel; osteogenic; pharmacologic; posttranscriptional; prevent; recruit; side effect; skills; therapeutic RNA; therapeutic target; therapeutically effective; tissue repair; translational study; wound healing

Patients with type 2 diabetes (T2D) have substantially higher incidence of bone disorders, including as much as a 64% greater risk of fracture as compared to those without T2D. High blood glucose levels adversely alter bone cell functions, causing decreased bone formation and delayed wound healing with poor quality tissue repair. Therefore, diabetic bone disease (DBD) is a serious health concern for more than 40 million people in the US and 370 million in the world currently afflicted with T2D. Current treatments for DBD include anti-resorptive drugs, selective estrogen receptor modulators, and anabolic (bone-forming) drugs. However, these drugs target either the bone-formation or bone-resorption pathway, not both. Moreover, these drugs have little direct effect on diabetic hyperglycemia, a major root cause of T2D bone disorders. Furthermore, recent data indicate some anti-diabetic drugs have side effects that actually increase fracture risk in T2D. Therefore, developing a safe and effective method to prevent DBD and restore and regenerate lost bone tissue in diabetics is critically important. Long noncoding RNAs (lncRNAs) are a family of non-protein-coding transcripts with length longer than 200 nucleotides. Emerging evidence suggests that lncRNAs play important roles in gene expression and are involved the pathogenesis of many human diseases. Currently, there are over 60 clinical trials using lncRNAs as a remedy. Our laboratory has recently identified and initially characterized a specific lncRNA that promotes osteogenesis and inhibits adipogenesis in diabetes. It can recruit KDM6B and KDM4B and influence the histone methylation of relevant genes. Its deficiency causes bone abnormalities and retards bone regeneration and delays wound healing in mouse models. This newly discovered lncRNA is therefore coined “lncR-DBD”, suggesting its potential roles in targeting the pathophysiology of diabetic bone disease. We have successfully generated a lncR-DBD gene knockout mouse line which will enable us to further dissect the biological function of this new lncRNA. Aim 1 will determine the cellular localization of lncR-DBD and explore the epigenetic pathways using the state-of-the-art approaches; Aim 2 will define the mechanisms and alterations in bone phenotype in lncR-DBD knockout mice; Aim 3 will use a novel nanohydrogel delivery system to investigate the therapeutic effects of lncR-DBD on bone wound repair and fracture healing in diabetic mice. The outcome of our study will provide a paradigm shift in current understanding of the pathophysiology of DBD and have a significant impact on the future treatment of this epidemic disease. Firstly, building on our preliminary findings that lncR-DBD plays a pivotal role in bone metabolism, this project will further reveal novel epigenetic mechanisms of DBD. Secondly, we will decipher the pathways of lncR-DBD modulating genes in the diabetic microenvironment, which will lead to discovery of new therapeutic targets. Finally, we will deliver the lncR-DBD mimics using a novel nanohydrogel system as a safe, effective means for lncRNA-based therapy. An interdisciplinary team of investigators with complementary and synergistic skills will conduct the studies.

2型糖尿病（T2D）患者的骨骼疾病发生率显著较高，包括 与没有T2D的人相比，骨折的风险高出64%。高血糖水平不利 改变骨细胞功能，导致骨形成减少和伤口愈合延迟，质量差 组织修复因此，糖尿病性骨病（DBD）是超过4000万人的严重健康问题。 美国和世界上3.7亿人目前患有T2D。目前DBD的治疗方法包括 抗再吸收药物、选择性雌激素受体调节剂和合成代谢（骨形成）药物。然而，在这方面， 这些药物靶向骨形成或骨吸收途径，而不是两者。此外，这些药物具有 对糖尿病性高血糖症（T2D骨骼疾病的主要根本原因）几乎没有直接影响。此外，最近的数据 表明一些抗糖尿病药物具有实际上增加T2D骨折风险的副作用。因此，我们认为， 开发一种安全有效的方法来预防糖尿病患者的DBD并恢复和再生丢失的骨组织 至关重要。长链非编码RNA（longnoncodingRNA，lncRNA）是一类长度为100 - 1000 bp的非蛋白质编码转录物， 超过200个核苷酸。新的证据表明lncRNA在基因表达中起重要作用 并参与许多人类疾病的发病机制。目前，有超过60个临床试验使用 lncRNA作为一种治疗方法。我们的实验室最近鉴定并初步表征了一种特异性lncRNA， 促进糖尿病中的骨生成并抑制脂肪生成。它可以招募KDM6B和KDM4B， 相关基因的组蛋白甲基化。它的缺乏会导致骨骼异常和骨骼发育迟缓 再生和延迟伤口愈合的小鼠模型。这种新发现的lncRNA因此被称为 “lncR-DBD”，表明其在靶向糖尿病性骨病的病理生理学中的潜在作用。我们有 成功地产生了lncR-DBD基因敲除小鼠系，这将使我们能够进一步剖析 这种新的lncRNA的生物学功能。目的1确定lncR-DBD的细胞定位， 使用最先进的方法的表观遗传途径;目标2将定义机制和改变 在lncR-DBD敲除小鼠的骨表型中; Aim 3将使用新型纳米水凝胶递送系统， 研究lncR-DBD对糖尿病小鼠骨创伤修复和骨折愈合的治疗作用。的 我们的研究结果将为目前对DBD病理生理学的理解提供一个范式转变， 对未来治疗这一流行病有重大影响。首先，在我们初步的基础上， 发现lncR-DBD在骨代谢中起着关键作用，该项目将进一步揭示新的表观遗传 DBD的机制其次，我们将从分子水平上对糖尿病患者lncR-DBD调控基因的通路进行研究， 微环境，这将导致新的治疗靶点的发现。最后，我们将把lncR-DBD 模拟使用一种新的纳米水凝胶系统作为一种安全，有效的手段为lncRNA为基础的治疗。一个 将由具有互补和协同技能的跨学科研究小组进行研究。